Method for producing alkyl acrylate dimers

Abstract

The invention relates to a method for producing alkyl acrylate dimers. The invention further relates to a method for producing hydrogenated alkyl acrylate dimers obtained by the dimerization method according to the invention. The invention further relates to a method for producing hydrolyzed alkyl acrylate dimers obtained by the dimerization method according to the invention.

Description

[0001] This application claims priority to the application filed on April 13, 2023, in Europe under No. 23167673.5, the entire contents of which are incorporated herein by reference for all purposes. TECHNICAL FIELD

[0002] The present invention relates to a process for the production of alkyl acrylate dimers. Furthermore, the present invention also relates to a process for the production of hydrogenated alkyl acrylate dimers obtained by the dimerization process according to the present invention. Furthermore, the present invention also relates to a process for the production of hydrolyzed alkyl acrylate dimers obtained by the dimerization process according to the present invention. BACKGROUND

[0003] The use of specific phosphines as catalysts for the dimerization of alkyl acrylates via Rauhut-Currier reaction has been described in the prior art.

[0004] US 3074999 A describes the dimerization of alkyl acrylates catalyzed by tertiary phosphines having three alkyl, three alicyclic or three aryl groups such as tributyl phosphine or triphenyl phosphine. However, these catalysts exhibit low activity in the dimerization reaction. With the disclosed process, moderate yields are reported which is a serious drawback for commercial production.

[0005] US 3227745 A describes the dimerization of alkyl acrylates catalyzed by tertiary phosphines in the presence of large amounts of tert-butanol as solvent. The disclosed tertiary phosphines are trialkyl phosphines. However, only a low conversion of the acrylates below 50% is achieved using the described process which is not suitable for an industrial production process.

[0006] US 3342853 A describes the dimerization of acrylates catalyzed by triaminophosphines which can be generated from PCI3 prior to the dimerization reaction. A yield of 70-80% of the methylene glutarate dimer is reported when the reaction is carried out at 60-65°C, however, large amounts of by-products are also formed. Furthermore, triaminophosphines are usually toxic and CMR agents (carcinogenic, mutagenic and reprotoxic agents) and when the catalyst is generated in situ, PCI3 is used as a precursor which is a very dangerous chemical. These are serious drawbacks for the commercialization and industrialization of the process.

[0007] US 3342854 A describes the dimerization of acrylic esters catalyzed by mono- or bis-amino phosphines. However, the low activity of diphenyl amino phosphines towards the dimerization of acrylic esters requires the use of higher phosphine loadings, which is a serious drawback for commercial production. This is shown by the two examples in this patent application using in situ generated dibutyl amino diphenyl phosphine catalyst or diethyl amino diphenyl phosphine catalyst, which both lead to dimer yields equal to or lower than 10%. Furthermore, a large amount of by-products is obtained using the method according to US 3342854 A.

[0008] Weiping Su et al. in "P(RNCH2CH2)3N: Catalysts for the Head-to-Tail Dimerization of Methyl Acrylate [P(RNCH2CH2)3N: Catalysts for the Head-to-Tail Dimerization of Methyl Acrylate]" J. Org. Chem. 2003, Vol. 68, pp. 9499-9501 describe the dimerization of methyl acrylate at room temperature in THF or dioxane as solvent using a phosphorus containing proazaphosphatrane as phosphine catalyst. At a catalyst loading of 1 mol% a yield of up to 82% is obtained. However, the catalyst described herein is rather complex and difficult to synthesize, leading to an overall expensive catalyst, which is a serious drawback for potential industrialization. Furthermore, using a low catalyst loading (1 mol%), the reaction kinetics is slow at room temperature, leading to long reaction times (up to 24 h), which is also a drawback for industrialized production. SUMMARY

[0009] The problem of the present invention is to provide an efficient process for the production of alkyl acrylate dimers using a highly active, robust, reusable, cheap and readily available catalyst, wherein the catalyst toxicity is relatively low, can be used at relatively low catalyst loadings and provides excellent selectivity.

[0010] In particular, the problem of the present invention is to provide a process for the preparation of alkyl acrylate dimers, wherein the use of large amounts of tertiary alcohols as solvent and relatively high catalyst loadings can be avoided. More particularly, the problem of the present invention is to provide an efficient process for the preparation of hydrogenated alkyl acrylate dimers and an efficient process for the preparation of hydrolyzed alkyl acrylate dimers.

[0011] It has now been found that these and other problems can be solved by the process of the present invention. The present invention relates to a process for the production of a dimer according to formula (II), the process comprising the step i) dimerizing an alkyl acrylate according to formula (I) using a catalyst according to formula (III) according to the following reaction scheme to obtain a dimer according to formula (II):

[0012] wherein R is an alkyl group; R1and R2are the same or different and are an aliphatic group or form together with the N atom a heteroaliphatic ring; R a is a hydrocarbyl group; R b is an aliphatic group or NR3R4, wherein R3and R4are the same or different and are an aliphatic group or form together with the N atom a heteroaliphatic ring; wherein the dimerization step i) is carried out in the presence of a compound A which is a tertiary alcohol or a silanol; and wherein an acid is added during the step i).

[0013] Further, the present invention also relates to a process as defined above, further comprising an initial step 0) of preparing the catalyst according to formula (III) by reacting a compound according to formula (IV) (IV) wherein X is chlorine, bromine or iodine, preferably chlorine; R a is as defined above; R c is X (for the case of a catalyst of formula (III) wherein R b is as defined above NR3R4) or R b (for the case of a catalyst of formula (III) wherein R b is an aliphatic group); with: - when R c is R b , an amine of formula (V): R1R2NH (V), wherein R1and R2are as defined above, or - when R c is X, both an amine of formula (V) and an amine of formula (V’): R3R4NH (V’), wherein R3and R4are as defined above.

[0014] Further, the present application provides a process for the production of a compound according to formula (VI), which comprises a process as defined above, followed by step ii) hydrogenation of the dimer according to formula (II) obtained in the dimerization step using H2 and a hydrogenation catalyst, such as a Pd-based catalyst (e.g. Pd / C, Pd / AI2O3, Pd / SiO2), a Ru-based catalyst (e.g. Ru / C), a Pt-based catalyst (e.g. Pt / C), a Ni-based catalyst (e.g. supported nickel or Raney nickel catalyst), a Co-based catalyst (e.g. supported cobalt or Raney cobalt), a Rh-based catalyst (e.g. Rh / C), an Ir-based catalyst (e.g. Ir / C), preferably Pd / C or Raney nickel, preferably Pd / C, to obtain a compound according to formula (VI) wherein R is as defined above.

[0015] The present application also relates to a process for the production of a compound according to formula (VII) (VII) and which comprises a further step iii) reacting the compound having formula (VI) with an amine having formula HNR 5 R 5 wherein R 5 and R 6 are identical or different and each is selected from a saturated or unsaturated, straight-chain or branched, optionally cyclic, optionally aromatic, optionally substituted hydrocarbon-based radical having an average number of carbon atoms in the range of from 1 to 36, with the proviso that R 5 and R 6 may optionally together form a ring member, which is optionally substituted and / or optionally contains a heteroatom.

[0016] R 5 and R 6 are identical or different, which can be in particular a radical selected from the group consisting of C1-C 12 alkyl, aryl, alkylaryl or arylalkyl or phenyl. The R 5 and R 6 radicals can optionally be substituted, in particular by a hydroxyl group.

[0017] R 5 and R 6 are identical or different, which can be in particular selected from the group consisting of methyl, ethyl, propyl (n-propyl), isopropyl, n-butyl, isobutyl, n-pentyl, amyl, isopentyl, hexyl, cyclohexyl or 2-hydroxyethyl. The R 5 and R 6The radicals can also be such that they form together with the nitrogen atom a morpholine, piperazine, pyrrolidine or piperidine radical. According to specific embodiments, R 5 = R 6 = methyl, or R 5 = R 6 = ethyl, or R 5 = R 6 = 2-hydroxyethyl. Good results are obtained when R 5 = R 6 = methyl.

[0018] Finally, the present application relates to a process for the production of a compound according to formula (VII) comprising a process as defined above followed by step ii') hydrolysis of the dimer according to formula (II) obtained in the dimerization step using an acid catalyst (such as a Lewis acid or a Brønsted acid, for example: HC1, H2S04, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, solid acid catalysts such as Amberlyst resins or zeolites, Nafion) to obtain a compound according to formula (VII) .

[0019] The present application is based on the recognition that a highly efficient process for the production of alkyl acrylate dimers using a highly active, robust, reusable, cheap and readily available catalyst is provided. The catalyst for the dimerization of alkyl acrylates is a compound according to formula (III) which is relatively less toxic, reusable, can be used at relatively low catalyst loadings and provides excellent selectivity. Furthermore, the present application provides a highly efficient process for the preparation of alkyl acrylate dimers using a compound according to formula (III) as catalyst, wherein the use of large amounts of tertiary alcohols relative to alkyl acrylate and the use of relatively high catalyst loadings can be avoided. Specifically, the molar amount of tertiary alcohol relative to alkyl acrylate can be reduced to a ratio of 0.01 : 1 and the catalyst loading can be reduced to 0.20 mol%. Finally, the present application provides a highly efficient process for the preparation of hydrogenated alkyl acrylate dimers and a highly efficient process for the preparation of hydrolyzed alkyl acrylate dimers. DETAILED DESCRIPTION

[0020] According to the present application, the term "about" means ± 10%, preferably ± 5%, and most preferably ± 2% of the specified value.

[0021] The present application relates to a process for the production of a dimer according to formula (II) comprising the step i) dimerization of an alkyl acrylate according to formula (I) using a catalyst according to formula (III) according to the following reaction scheme to obtain a dimer according to formula (II):

[0022] wherein R is an alkyl group; R1and R2are the same or different and are aliphatic groups or form together with the N atom a heteroaliphatic ring; R a is a hydrocarbyl group; R b is an aliphatic group or NR3R4, wherein R3and R4are the same or different and are aliphatic groups or form together with the N atom a heteroaliphatic ring; wherein the dimerization step i) is carried out in the presence of a compound A which is a tertiary alcohol or a silanol; and wherein an acid is added during the step i).

[0023] Preferably, in the process for producing a dimer according to formula (II) as defined herein, compound A is a tertiary alcohol, such as tert-butanol, tert-amyl alcohol or pinacol and more preferably tert-butanol.

[0024] Preferably, in the process for producing a dimer according to formula (II) as defined herein, the molar ratio [compound A] / [alkyl acrylate according to formula (I)] is selected from about 4 : 1 to about 0.01 : 1, preferably about 2 : 1 to about 0.1 : 1, and more preferably about 0.5 : 1 to about 0.1 : 1, and in particular about 0.5 : 1 to about 0.2 : 1.

[0025] Preferably, in the process for producing a dimer according to formula (II) as defined herein, R is a C1-C 18 , more preferably a C1-C8alkyl group, still more preferably a C1-C4alkyl group and most preferably a methyl group.

[0026] Preferably, in the process for producing a dimer according to formula (II) as defined herein, R is a methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, 2-ethylhexyl, octyl, decyl, dodecyl, tert-dodecyl, tetradecyl, hexadecyl or octadecyl group, more preferably a methyl, ethyl, isopropyl, butyl or 2-ethylhexyl group, still more preferably a methyl, ethyl, isopropyl or butyl group, most preferably a methyl group.

[0027] Preferably, in the process for producing a dimer according to formula (II) as defined herein, R1and R2are the same straight chain or branched alkyl group comprising 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, most preferably an ethyl group.

[0028] Preferably, in the process for producing a dimer according to formula (II) as defined herein, R1and R2together with the N atom form a heteroaliphatic ring comprising 3 to 5 carbon atoms, preferably 4 carbon atoms.

[0029] Preferably, in the process for producing a dimer according to formula (II) as defined herein, R a is an aromatic or aliphatic group, more preferably an aromatic group, still more preferably selected from the group consisting of phenyl, tolyl, xylyl, mesityl, cumyl, pentamethylphenyl, 2,6-diisopropylphenyl, t-butylphenyl, di-t-butylphenyl, methoxyphenyl, dimethoxyphenyl, methoxytolyl, methylenedioxyphenyl, biphenyl, nitrophenyl, halogen substituted phenyl, trifluoromethylphenyl, naphthyl, pyridyl, furanyl, pyrrolyl, thienyl, 2-indolyl, benzofuranyl and all positional isomers thereof.

[0030] Preferably, R aselected from the group consisting of phenyl; o-, m- or p-tolyl; xylyl, including all positional isomers, such as 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2,6-xylyl, 3,4-xylyl and 3,5-xylyl; 3-methyl-4-methoxyphenyl, 2-methyl-4-methoxyphenyl, 2-methyl-3-methoxyphenyl, 4-methyl-3-methoxyphenyl, 5-methyl-3-methoxyphenyl, 6-methyl-3-methoxyphenyl, 2-methoxy-3-methylphenyl, 2-methoxy-4-methylphenyl, 2-methoxy-5-methylphenyl, 2-methoxy-6-methylphenyl; mesityl, including all positional isomers, such as 2,3,4-mesityl, 2,3,5-mesityl, 2,3,6-mesityl, 2,4,5-mesityl, 2,4,6-mesityl and 3,4,5-mesityl; duryl, including all positional isomers, such as 2,3,4,5-tetramethylphenyl, 2,3,4,6-tetramethylphenyl and 2,3,5,6-tetramethylphenyl; pentamethylphenyl, 2,6-diisopropylphenyl; o-, m- or p-tert-butylphenyl; 2,3-di-tert-butylphenyl, 2,4-di-tert-butylphenyl, 2,5-di-tert-butylphenyl, 2,6-di-tert-butylphenyl, 3,4-di-tert-butylphenyl and 3,5-di-tert-butylphenyl; o-, m- or p-methoxyphenyl; o-, m- or p-chlorophenyl; 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl; 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl; o-, m- or p-nitrophenyl; o-, m- or p-biphenylyl; o-, m- or p-trifluoromethylphenyl, o-, m- or p-fluorophenyl; 1- or 2-naphthyl; 2-, 3- or 4-pyridyl; 2- or 3-furyl; 1-, 2- or 3-pyrrolyl; 2- or 3-thienyl; 2- or 3-indolyl; 2- or 3-benzofuryl; preferably phenyl; o-, m- or p-tolyl; or xylyl and its isomeric positions.

[0031] Preferably, in the process for the production of a dimer according to formula (II) as defined herein, R b is NR3R4, wherein R3and R4are the same or different and are aliphatic groups or form together with the N atom a heteroaliphatic ring, more preferably R3and R4are the same linear or branched alkyl group comprising 1 to 6 carbon atoms, still more preferably 1 to 3 carbon atoms, most preferably ethyl.

[0032] Preferably, in the process for producing a dimer according to formula (II) as defined herein, R a is phenyl, R1and R2are ethyl and R b is NR3R4, wherein R3and R4are ethyl.

[0033] Preferably, in the process for producing a dimer according to formula (II) as defined herein, the catalyst according to formula (III) is a compound selected from the group consisting of compounds according to formulae (VIII) to (XIV): .

[0034] More preferably, in the process for producing a dimer according to formula (II) as defined herein, the catalyst according to formula (III) is a compound selected from the group consisting of compounds according to formulae (IX) and (XI) to (XIV), still more preferably a compound selected from the group consisting of compounds according to formulae (XI), (XII) and (XIV), even more preferably a compound selected from the group consisting of compounds according to formulae (XI) and (XIV), most preferably the catalyst according to formula (III) is a compound according to formula (XIV).

[0035] Preferably, in the process for producing a dimer according to formula (II) as defined herein, the dimerization step i) is carried out in an organic solvent, more preferably an aprotic solvent, still more preferably selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, 1,4-dioxane, pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, benzene and acetonitrile, even more preferably MeTHF, anisole and toluene, most preferably MeTHF and anisole.

[0036] Preferably, in the process for producing a dimer according to formula (II) as defined herein, the dimerization step i) is carried out at a temperature in the range of about 20 °C to about 120 °C, more preferably about 20 °C to about 80 °C, still more preferably about 25 °C to about 60 °C, most preferably about 30 °C to about 60 °C.

[0037] Preferably, in the process for the production of a dimer according to formula (II) as defined herein, in step i), the catalyst according to formula (III) is used in a catalyst loading of 0.20 mol% to 1.00 mol%, more preferably of about 0.25 mol% to about 0.90 mol%, still more preferably of about 0.30 mol% to about 0.90 mol%, even more preferably of about 0.30 mol% to about 0.80 mol%, even still more preferably of about 0.30 mol% to about 0.70 mol%, even still more preferably of about 0.30 mol% to about 0.60 mol%, most preferably of about 0.30 mol% to 0.50 mol%, relative to the alkyl acrylate according to formula (I).

[0038] Preferably, in the process for the production of a dimer according to formula (II) as defined herein, the dimerization step i) is carried out under anhydrous conditions and in the absence of oxygen.

[0039] The Applicant has found that better results can be obtained if an acid is added during the dimerization step i). The acid can be selected from inorganic acids, like HC1, HN03, H3P04, H2S04, H3B03, HF, HBr, HCIO4, HI, NaHSO4, KHSO4, NH4HSO4, NaHSO3, KHSO3, H3P03, H3P02, and the like. Alternatively, it can be selected from organic acids, like acetic acid, malic acid, tartaric acid, lactic acid, pyruvic acid, citric acid, formic acid, uric acid, ascorbic acid, gluconic acid, itaconic acid, propionic acid, butyric acid, (meth)acrylic acid, terephthalic acid, benzoic acid, methylbenzoic acid, levulinic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid. It can also be a heterogeneous solid acid, like Amberlyst resins, and the like.

[0040] Preferably, the process for the production of a dimer according to formula (II) as defined herein further comprises an initial step 0) of preparing the catalyst according to formula (III) by reacting a compound according to formula (IV) (IV) wherein X is chlorine, bromine or iodine, preferably chlorine; R a is a hydrocarbyl group; R c is X (for the case of a catalyst of formula (III) wherein R b is NR3R4as defined above) or R b (for the case of a catalyst of formula (III) wherein R bis an aliphatic group) ; with the following: - when R c is R b , an amine of formula (V): R1R2NH (V), wherein R1and R2are as defined herein, or - when R c is X, both an amine of formula (V) and an amine of formula (V'): R3R4NH (V'), wherein R3and R4are as defined herein.

[0041] Preferably, in the process for producing a dimer according to formula (II) as defined herein, step 0) and step i) are consecutive steps performed after step 0) without isolating the catalyst.

[0042] Preferably, in the process for producing a dimer according to formula (II) as defined herein, R c is X.

[0043] Preferably, in the process for producing a dimer according to formula (II) as defined herein, step 0) is performed in an organic solvent, more preferably an aprotic solvent, still more preferably selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, dioxane, pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, benzene, and acetonitrile, even more preferably MeTHF, anisole, and toluene, most preferably MeTHF and anisole.

[0044] Preferably, in the process for producing a dimer according to formula (II) as defined herein, step 0) is performed at a temperature ranging from about 20°C to about 100°C, preferably from about 20°C to 80°C, more preferably from about 25°C to 60°C, most preferably at a temperature of about 40°C.

[0045] Preferably, in the process for producing a dimer according to formula (II) as defined herein, step 0) is performed by slow addition of the reactant of formula (IV) to a solution of the amine R1R2NH in an aprotic solvent, wherein R c is R b and R bWhen Rcis an aliphatic group, the amines are used in an amount equal to or greater than 2 equivalents relative to the reactant of formula (IV). Step (0) can also be performed by slowly adding the reactant of formula (IV) to a solution containing both amines R1R2NH and R3R4NH in an aprotic solvent, wherein the total amount of amines is equal to or greater than 4 equivalents relative to the reactant of formula (IV) when Rc in (IV) is X.

[0046] Preferably, in the process for the production of a dimer according to formula (II) as defined herein, step 0) is performed under anhydrous conditions and in the absence of oxygen.

[0047] Preferably, in the process for the production of a dimer according to formula (II) as defined herein, step 0) comprises a filtration step to remove the formed ammonium salt by-product before performing step i).

[0048] Further, the present application provides a process for the production of a compound according to formula (VI), comprising a process for the production of a dimer according to formula (II) as defined herein, followed by step ii) hydrogenation of the dimer according to formula (II) obtained in the dimerization step using H2 and a hydrogenation catalyst, such as a Pd-based catalyst (e.g. Pd / C, Pd / AI2O3, Pd / SiO2), a Ru-based catalyst (e.g. Ru / C), a Pt-based catalyst (e.g. Pt / C), a Ni-based catalyst (e.g. supported nickel or Raney nickel catalyst), a Co-based catalyst (e.g. supported cobalt or Raney cobalt), a Rh-based catalyst (e.g. Rh / C), an Ir-based catalyst (e.g. Ir / C), preferably Pd / C or Raney nickel, preferably Pd / C, to obtain a compound according to formula (VI) wherein R is as defined herein.

[0049] In a preferred embodiment, the process for the production of a compound according to formula (VI) further comprises step iii') hydrolysis of the hydrogenated dimer according to formula (VI) obtained in step ii) using an acid catalyst (such as a Lewis acid or a Brønsted acid, for example: HC1, H2SO4, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, solid acidic catalysts such as Amberlyst resins, zeolites or Nafion) to obtain a compound according to formula (XV) .

[0050] Finally, the present application relates to a process for the production of a compound according to formula (VII), comprising a process as defined above, followed by step ii') hydrolysis of the dimer according to formula (II) obtained in the dimerization step using an acid catalyst (such as a Lewis acid or a Brønsted acid, for example: HC1, H2S04, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, solid acid catalysts such as Amberlyst resins or zeolites, Nafion) to obtain a compound according to formula (VII) .

[0051] In a preferred embodiment, the process for the production of a compound according to formula (VII) further comprises step iii") hydrogenation of the hydrolyzed dimer according to formula (VII) obtained in step ii') using H2and a hydrogenation catalyst, such as a Pd-based catalyst (e.g. Pd / C, Pd / AI2O3, Pd / SiO2), a Ru-based catalyst (e.g. Ru / C), a Pt-based catalyst (e.g. Pt / C), a Ni-based catalyst (e.g. supported nickel or Raney nickel catalyst), a Co-based catalyst (e.g. supported cobalt or Raney cobalt), a Rh-based catalyst (e.g. Rh / C), an Ir-based catalyst (e.g. Ir / C), preferably Pd / C or Raney nickel, preferably Pd / C, to obtain a compound according to formula (XV) .

[0052] Examples 1. Aminophosphine catalyzed dimerization of methyl acrylate General protocol for phosphine screening studies: a) from dichlorophosphine via symmetric bis-amino phosphine catalyzed dimerization: All reactions were carried out in carefully dried vessels under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried using 4A molecular sieves and tert-butanol was distilled under argon before each reaction. Dichlorophosphine and amines were used as received.

[0053] To a 25 mL two-necked round bottom flask was added: • 3 mL of 2-methyltetrahydrofuran • Dichlorophosphine precursor (1.8 mmol, 0.01 equivalents relative to methyl acrylate).

[0054] To a 50 mL three-necked round bottom flask, equipped with a magnetic stirring device, was added: • 1 mL of 2-methyltetrahydrofuran • 4 equivalents of the desired amine relative to the dichlorophosphine precursor (7.2 mmol).

[0055] Under stirring (1400 rpm), the dichlorophosphine solution was added gradually to the amine solution over 1 h while keeping the temperature of the reaction medium below 40°C (exothermic reaction). Upon addition of the dichlorophosphine to the amine solution, a white precipitate corresponding to the insoluble ammonium chloride salt by-product was formed. At the end of the addition, the mixture was then stirred at ambient temperature and the progress of the reaction was monitored by 31 P NMR monitoring of the reaction progress (for the amino phosphines studied 31 P chemical shifts, see Table 1 below).

[0056] Upon completion of the phosphine formation (this generally requires stirring at room temperature for 1 h after the chlorophosphine addition for the non-hindered amines and 2 h for the more sterically hindered amines), the mixture was then filtered via cannula into a 100 mL three-necked round bottom flask equipped with a magnetic stirrer, condenser, heater, and temperature probe and containing 32 mL of molten tert-butanol (2: 1 v / v relative to methyl acrylate). The mixture was then allowed to stir at 60°C. 15.95 mL of methyl acrylate (15.15 g, 0.176 moles, 1 equivalent) was added carefully (exothermic) to the reactor over 1 h and the progress of the reaction was monitored by 1 HNMR monitoring of the reaction progress. The reaction was continued until the progress stopped or the reaction was 1 day. Then, the product was isolated by 1 H NMR estimated the conversion of methyl acrylate by integration of the methylene protons of the product and the methylene protons in the starting methyl acrylate.

[0057] NMR spectra of the products: 1 H NMR (CDC13, 400 MHz) δ (ppm): 6.03 (s, 1H), 5.46 (s, 1H), 3.60 (s, 3H), 3.51 (s, 3H), 2.48 (t, J = 7.6 Hz, 2H), 2.37 (t, J = 7.6 Hz, 2H).

[0058] b) from mono-chlorophosphine via mono-amino phosphine catalyzed dimerization: All reactions were performed in carefully dried vessels under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried using 4A molecular sieves and the tert-butanol was distilled under argon prior to each reaction. Mono-chlorophosphines and amines were used as received.

[0059] To a 25 mL two-necked round bottom flask was added: • 3 mL of 2-methyltetrahydrofuran • Mono-chlorophosphine precursor (1.8 mmol, 0.01 equivalent relative to methyl acrylate).

[0060] Into a 50 mL three-necked round bottom flask equipped with a magnetic stirring device was added: • 1 mL of 2-methyltetrahydrofuran • 2 equivalents of the desired amine (3.6 mmol) relative to the mono-chlorophosphine precursor.

[0061] Under stirring (1400 rpm), the mono-chlorophosphine solution was gradually added to the amine solution over 1 h while keeping the temperature of the reaction medium below 40 °C (exothermic reaction). Upon addition of the mono-chlorophosphine to the amine solution, a white precipitate corresponding to the insoluble ammonium chloride salt by-product was formed. At the end of the addition, the mixture was then stirred at ambient temperature and the progress of the reaction was monitored by 31 P NMR.

[0062] Upon completion of the phosphine formation (1 h of stirring at room temperature is typically required for non-hindered amines and 2 h of stirring for sterically more hindered amines upon addition of the mono-chlorophosphine), the mixture was then filtered via cannula into a 100 mL three-necked round bottom flask equipped with a magnetic stirrer, a condenser, a heater and a temperature probe and containing 32 mL of molten tert-butanol (2 : 1 v / v relative to methyl acrylate). The mixture was then allowed to stir at 60 °C. 15.95 mL of methyl acrylate (15.15 g, 0.176 mol, 1 equivalent) was immediately added (exothermic) to the reactor over 1 h and the progress of the reaction was monitored by 1 H NMR. The reaction was continued until the progress stopped or the reaction was 1 day. Then, the conversion of methyl acrylate was estimated by 1 H NMR by integration of the methylene protons of the product and the methylene protons in the starting methyl acrylate.

[0063] c) from dichlorophosphine, diisopropylamine and additional amine via asymmetric bis-amino phosphine catalyzed dimerization: All reactions were performed in carefully dried vessels under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried using 4A molecular sieves and the tert-butanol was distilled under argon prior to each reaction. Dichlorophosphine and amines were used as received.

[0064] Into a 25 mL two-necked round bottom flask was added: • 3 mL of 2-methyltetrahydrofuran • Dichlorophosphine precursor (1.8 mmol, 0.01 equivalent relative to methyl acrylate).

[0065] Into a 50 mL three-necked round bottom flask equipped with a magnetic stirring device was added: • 1 mL of 2-methyltetrahydrofuran • 3 equivalents of diisopropylamine (5.4 mmol) relative to the dichlorophosphine precursor.

[0066] The phosphorous dichloride solution was added gradually to the amine solution over 1 hour under stirring (1400 rpm) while keeping the temperature of the reaction medium below 40°C (exothermic reaction). Upon addition of the phosphorous dichloride to the amine solution, a white precipitate corresponding to the insoluble ammonium chloride salt by-product (diisopropylammonium chloride in the case of the present application) was formed. The mixture was then stirred at ambient temperature and the reaction progress was monitored by 31 P NMR. The formation of the intermediate chloro(diisopropylamino)phosphine was confirmed by 31 P NMR (e.g. a singlet was observed at +132.5 ppm for chlorophenyl(diisopropylamino)phosphine).

[0067] Upon completion of the chloroamino phosphine intermediate formation, which generally requires 1 h00 stirring at room temperature upon addition of the phosphorous dichloride, 1 equivalent of a second amine (1.8 mmol) was added to the mixture at room temperature under stirring and the reaction mass was stirred for another hour at room temperature.

[0068] Upon completion of the bis-amino phosphine, the mixture was then filtered via a cannula into a 100 mL three-necked round bottom flask equipped with a magnetic stirrer, a condenser, a heater and a temperature probe and containing 32 mL of molten tert-butanol (2 : 1 v / v relative to methyl acrylate). The mixture was then allowed to stir at 60°C. 15.95 mL of methyl acrylate (15.15 g, 0.176 mol, 1 equivalent) were carefully added (exothermic) to the reactor over 1 hour and the reaction was monitored by 1 H NMR. The reaction was continued until progress ceased or the reaction was 1 day old. Then, the conversion of the methyl acrylate was estimated by integration of the methylene protons of the product and the methylene protons in the starting methyl acrylate. 1 H NMR. The conversion of the methyl acrylate was estimated by integration of the methylene protons of the product and the methylene protons in the starting methyl acrylate.

[0069] To confirm that the target catalyst was successfully synthesized, the 31 P NMR of the crude reaction medium was analyzed. Indeed, this parameter ( 31 P NMR chemical shift) is characteristic of the synthesized amino phosphine and the area under the peak is directly proportional to the molar concentration of the amino phosphine in solution. The 31 P NMR spectrum was recorded using a Bruker Avance 400 MHz spectrometer.

[0070] Additionally, the - NMR yield of phosphine (%) corresponding to the molar selectivity of the amino phosphine synthesis reaction was inferred from the area under the peak in the 31 P NMR spectrum recorded for the Me-THF solution before transfer to the dimerization reactor; - the maximum conversion of the acrylic ester dimerization in some of the experiments presented above in Table 1, which corresponds to the maximum conversion of methyl acrylate measured by H NMR. 1 H NMR measured maximum conversion of methyl acrylate.

[0071] The ratio of t-BuOH : enoate is also given in v : v (and in mol / mol). t The ratio of t-BuOH : enoate is also given in v : v (and in mol / mol).

[0072] For the present application 4.4, the reaction was started with an initial dichlorophenyl phosphine loading of 0.5 mol% followed by the addition of an additional amount of methyl acrylate (0.5 equivalent to reach a 0.33 mol% of the initial dichlorophenyl phosphine loading) after 20 h of reaction time.

[0073] All the results are compiled in the following Table 1 : Table 1 : Aminophosphine screening study results - dimerization process (Cp = comparative example) All the phosphines were synthesized.

[0074] The chloro diphenyl phosphine precursor gave the aminophosphine only in moderate yield by reaction with diisopropylamine (compound 1) and could not provide a good catalytic activity. The chloro diphenyl phosphine precursor reacted with pyrrolidine (compound 2) and also could not provide a good catalytic activity. On the other hand, the aminophosphines according to the present application (present application 1 to 7) provided quite good catalytic activities.

[0075] The best system showing the best performance is the diisopropylamino-pyrrolidinyl-phenyl phosphine (present application 4.1 to 4.4). Surprisingly, it has been observed that with the diisopropylamino-pyrrolidinyl-phenyl phosphine (present application 4.4) a 91% of acrylic ester conversion was reached with only 0.33 mol% of the initial dichlorophosphine loading. Moreover, it was observed that this phosphine is quite robust allowing an easier handling and even allowing its recycling for several batches.

[0076] The presence of t-butanol during the dimerization reaction allows to increase the selectivity of the reaction towards the expected dimer. Surprisingly, it is still possible to find suitable conditions allowing the use of t t-BuOH with a very small amount of basic aminophosphine without affecting the catalytic activity of the phosphine and providing a good selectivity.

[0077] d) Optimization of the dimerization reaction: in t-butanol (1 : 4 v / v t BuOH : methyl acrylate = 0.24 mol Methyl acrylate dimerization catalyzed by bis(diethylamino)phenyl phosphine (0.7 mol% of initial dichlorophenyl phosphine precursor relative to methyl acrylate) in t-butanol (1 : 8 v / v t-BuOH : methyl acrylate = 0.12 mol (t-BuOH) / mol (methyl acrylate)) at 45 °C, average of 2 batches. Methyl acrylate dimerization catalyzed by bis(diethylamino)phenyl phosphine (0.7 mol% of dichlorophenyl phosphine precursor relative to methyl acrylate) in t-butanol (1 : 8 v / v t-BuOH : methyl acrylate = 0.12 mol (t-BuOH) / mol (methyl acrylate)) at 45 °C, average of 2 batches.

[0078] All reactions were carried out in carefully dried vessels and under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried using 4A molecular sieves and the tert-butanol was distilled under argon prior to each reaction. Dichlorophenylphosphine and diethylamine were used as received.

[0079] To a 50 mL two-necked round bottom flask was added: • 15 mL of 2-methyltetrahydrofuran • 4.2 mL of dichlorophenylphosphine (5.57 g, 0.031 moles, 0.007 equivalents).

[0080] To a 100 mL three-necked round bottom flask equipped with a magnetic stirring apparatus was added: • 20 mL of 2-methyltetrahydrofuran • 12.9 mL of diethylamine (9.1 g, 0.124 moles, 0.028 equivalents) (4 equivalents relative to dichlorophenylphosphine).

[0081] The 2-methyltetrahydrofuran solution of dichlorophenylphosphine was gradually added to the diethylamine solution over 1 h with stirring (1400 rpm) while maintaining the temperature of the reaction medium below 40 °C (exothermic reaction). A white precipitate corresponding to the ammonium chloride salt byproduct (in the case of diethylammonium chloride) formed upon addition of the dichlorophenylphosphine. At the end of the addition, the mixture was then stirred at ambient temperature and the reaction progress was monitored by NMR.

[0082] Upon completion of the formation of bis-(diethylamino)phenylphosphine, which required 1 h of stirring at room temperature after addition of the dichlorophenylphosphine, the mixture was filtered via cannula into a 500 mL double-jacketed reactor maintained at 45 °C, which was equipped with a temperature probe, a condenser, and a mechanical stirrer (propeller with four tilted plows) and contained: • 100 mL of distilled tert-butanol (1 : 4 v / v tert-butanol : methyl acrylate) • 400 mL of methyl acrylate (380.8 g, 4.42 moles, 1 equivalent) The mixture was then continuously stirred at 45 °C for 19 h. The reaction progress was monitored by 1 H NMR. The conversion of methyl acrylate was estimated by 1 H NMR by integration of the methylene protons of the product and the methylene protons in the starting methyl acrylate. According to NMR, the conversion of the starting methyl acrylate was about 92 mol%.

[0083] At the end of the reaction, the volatiles were distilled off tBuOH, Me-THF and unconverted methyl acrylate), recovering 31 g of unreacted methyl acrylate. The desired product (dimethyl 2-methylene glutarate) was then distilled under vacuum (160°C, 15 mbar), obtaining 283 g of analytically pure product (isolated yield = 75%). The high-boiling by-products (methyl acrylate oligomers) remaining in the distillation vessel were approximately 57 g (15%).

[0084] 1 H NMR (CDC13, 400 MHz) δ (ppm): 6.03 (s, 1H), 5.46 (s, 1H), 3.60 (s, 3H), 3.51 (s, 3H), 2.48 (t, J = 7.6 Hz, 2H), 2.37 (t, J = 7.6 Hz, 2H).

[0085] 13 C NMR (CDC13, 101 MHz) δ (ppm): 172.73, 166.75, 138.76, 125.56, 51.59, 51.26, 32.66 and 27.17.

[0086] Methyl acrylate dimerization catalyzed by bis(diethylamino)phenyl phosphine (0.7 mol% of dichlorophenyl phosphine precursor relative to methyl acrylate) in t-butanol (1 : 8 v / v t-BuOH : methyl acrylate = 0.12 mol (t-BuOH) / mol (methyl acrylate)) at 45 °C, average of 2 batches. Methyl acrylate dimerization catalyzed by bis(diethylamino)phenyl phosphine (0.7 mol% of dichlorophenyl phosphine precursor relative to methyl acrylate) in t-butanol (1 : 8 v / v t-BuOH : methyl acrylate = 0.12 mol (t-BuOH) / mol (methyl acrylate)) at 45 °C, average of 2 batches. Methyl acrylate dimerization catalyzed by bis(diethylamino)phenyl phosphine (0.7 mol% of dichlorophenyl phosphine precursor relative to methyl acrylate) in t-butanol (1 : 8 v / v t-BuOH : methyl acrylate = 0.12 mol (t-BuOH) / mol (methyl acrylate)) at 45 °C, average of 2 batches.

[0087] All reactions were carried out in carefully dried vessels and under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried using 4A molecular sieves and the tert-butanol was distilled under argon before each reaction. Dichlorophosphine and diethylamine were used as received.

[0088] To a 50 mL two-necked round-bottom flask were added: • 15 mL of 2-methyltetrahydrofuran • 4.2 mL of dichlorophosphine (5.57 g, 0.031 moles, 0.007 equivalents).

[0089] To a 100 mL three-necked round-bottom flask, equipped with a magnetic stirring device, were added: • 20 mL of 2-methyltetrahydrofuran • 12.9 mL of diethylamine (9.1 g, 0.124 moles, 0.028 equivalents) (4 equivalents with respect to dichlorophosphine).

[0090] Under stirring (1400 rpm), the 2-methyltetrahydrofuran solution of dichlorophenylphosphine was gradually added to the diethylamine solution in 1 hour while keeping the temperature of the reaction medium below 40°C (exothermic reaction). After the addition of dichlorophenylphosphine, a white precipitate corresponding to the ammonium chloride salt by-product (in the case of diethylammonium chloride) was formed. At the end of the addition of dichlorophosphine, the mixture was then stirred at ambient temperature and the reaction progress was monitored by NMR.

[0091] After the formation of bis-(diethylamino)phenylphosphine was complete (which required 1 h of stirring at room temperature after the addition of dichlorophenylphosphine), the mixture was filtered via a cannula into a 500 mL double-jacketed reactor maintained at 45°C, equipped with a temperature probe, a condenser and a mechanical stirrer (propeller with four tilted plows) and containing: • 50 mL of distilled tert-butanol (1 : 8 v / v tert-butanol : methyl acrylate) • 400 mL of methyl acrylate (380.8 g, 4.42 moles, 1 equivalent).

[0092] The mixture was then continuously stirred at 45°C for 19 hours. The reaction progress was monitored by 1 H NMR. The conversion of methyl acrylate was estimated by integration of the methylene protons of the product and the methylene protons in the starting methyl acrylate by 1 H NMR. According to NMR, the conversion of the starting methyl acrylate was about 88 mol%. At the end of the reaction, the volatiles (t-BuOH, Me-THF and unconverted methyl acrylate) were distilled off, thus recovering 44 g of unreacted methyl acrylate. t

[0093] The desired product (dimethyl 2-methylene glutarate) was then distilled under vacuum (160°C, 15 mbar) to give 271 g of analytically pure product (isolated yield = 71%). The high-boiling by-products (methyl acrylate oligomers) remaining in the distillation vessel amounted to 59 g (16%).

[0094] 1 H NMR (CDC13, 400 MHz) δ (ppm): 6.03 (s, 1H), 5.46 (s, 1H), 3.60 (s, 3H), 3.51 (s, 3H), 2.48 (t, J = 7.6 Hz, 2H), 2.37 (t, J = 7.6 Hz, 2H).

[0095] 13 ​C NMR (CDCI3, 101 MHz) δ (ppm): 172.73, 166.75, 138.76, 125.56, 51.59, 51.26, 32.66 and 27.17.

[0096] f) in tert-butanol (1 : 8 v / v t BuOH : methyl acrylate = 0.12 mol ( t BuOH) / mol (acrylic acid) Methyl acrylate dimerization catalyzed by bis(diethylamino)phenyl phosphine (0.7 mol% of dichlorophenyl phosphine precursor relative to methyl acrylate) in t-butanol (1 : 8 v / v t-BuOH : methyl acrylate = 0.12 mol (t-BuOH) / mol (methyl acrylate)) at 45 °C, average of 2 batches. Methyl acrylate dimerization catalyzed by bis(diethylamino)phenyl phosphine (0.7 mol% of dichlorophenyl phosphine precursor relative to methyl acrylate) in t-butanol (1 : 8 v / v t-BuOH : methyl acrylate = 0.12 mol (t-BuOH) / mol (methyl acrylate)) at 45 °C, average of 2 batches.

[0097] All reactions were carried out in carefully dried vessels and under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried using 4A molecular sieves and the tert-butanol was distilled under argon prior to each reaction. Dichlorophenyl phosphine and diethylamine were used as received.

[0098] Into a 25 mL two-necked round bottom flask was added: • 8 mL of 2-methyltetrahydrofuran • 2.1 mL of dichlorophenyl phosphine (2.79 g, 0.0155 moles, 0.007 equivalents).

[0099] Into a 50 mL three-necked round bottom flask equipped with a magnetic stirring apparatus was added: • 10 mL of 2-methyltetrahydrofuran • 6.5 mL of diethylamine (4.6 g, 0.062 moles, 0.028 equivalents) (4 equivalents relative to dichlorophenyl phosphine).

[0100] The 2-methyltetrahydrofuran solution of dichlorophenyl phosphine was gradually added to the diethylamine solution over 1 h with stirring (1400 rpm) while maintaining the temperature of the reaction medium below 40°C (exothermic reaction). A white precipitate corresponding to the diethylammonium chloride salt byproduct formed upon addition of the dichlorophenyl phosphine. The mixture was then stirred at ambient temperature and the reaction progress was monitored by NMR.

[0101] Upon completion of the formation of bis-(diethylamino)phenyl phosphine, which required 1 h of stirring at room temperature after addition of the dichlorophenyl phosphine, the mixture was filtered via cannula into a 500 mL double-jacketed reactor maintained at 60°C, equipped with a temperature probe, condenser and mechanical stirrer (propeller with four tilted plows) and containing: • 25 mL of distilled tert-butanol (1 : 8 v / v tert-butanol : methyl acrylate) • 200 mL of methyl acrylate (190 g, 2.21 moles, 1 equivalent).

[0102] The mixture was then stirred at 60°C for 20 h. The reaction progress was monitored by 1 H NMR. The reaction progress was monitored by1 HNMR The conversion of methyl acrylate was estimated by integration of the methylene protons of the product and the methylene protons in the starting methyl acrylate. According to NMR, the conversion of the starting methyl acrylate was about 95 mol% (average of 2 batches). At the end of the reaction, the volatiles were distilled off t - BuOH, Me-THF and unconverted methyl acrylate).

[0103] The desired product (dimethyl 2-methylene glutarate) was then distilled under vacuum (140°C, 5 mbar) to give 137 g of analytically pure product (average of 2 batches, isolated yield = 72%). The high-boiling by-products (mainly methyl acrylate oligomers) remaining in the distillation vessel amounted to 40 g (21%, average of 2 batches).

[0104] g) in tert-butanol (1 : 4 v / v t BuOH : methyl acrylate = 0.24 mol ( t BuOH) / mol (acrylic acid) Catalytic hydrogenation of dimethyl 2-methylene glutarate to dimethyl 2-methyl glutarate Synthesis of 2-methylene glutaric acid from dimethyl 2-methylene glutarate

[0105] All reactions were carried out in carefully dried vessels and under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried using 4A molecular sieves and the tert-butanol was distilled under argon before each reaction. Dichlorophosphine and diethylamine were used as received.

[0106] Into a 50 mL two-necked round-bottomed flask were added: • 20 mL of 2-methyltetrahydrofuran • 5.43 mL of dichlorophosphine (7.17 g, 0.04 mol, 0.009 equivalent).

[0107] Into a 100 mL three-necked round-bottomed flask equipped with a magnetic stirring device were added: • 20 mL of 2-methyltetrahydrofuran • 16.6 mL of diethylamine (11.7 g, 0.16 mol, 0.036 equivalent) (4 equivalents relative to dichlorophosphine).

[0108] The solution of dichlorophosphine in 2-methyltetrahydrofuran was gradually added to the diethylamine solution over 1 hour under stirring (1400 rpm) while keeping the temperature of the reaction medium below 40°C (exothermic reaction). A white precipitate corresponding to the diethylammonium chloride salt by-product formed after the addition of dichlorophosphine. At the end of the addition of dichlorophosphine, the mixture was then stirred at ambient temperature and the progress of the reaction was monitored by NMR.

[0109] After the formation of bis-(diethylamino)phenyl phosphine was complete (this required stirring at room temperature for 1 h after the addition of dichlorophenyl phosphine), the mixture was filtered via a cannula into a 500 mL double-jacketed reactor maintained at 30°C, which was equipped with a temperature probe, condenser, and mechanical stirrer (propeller with four tilted plows) and contained: • 100 mL of distilled tert-butanol (1 : 4 v / v tert-butanol : methyl acrylate) • 400 mL of methyl acrylate (380.8 g, 4.42 moles, 1 equivalent).

[0110] The mixture was then continuously stirred at 30°C for 20 hours. The reaction progress was monitored by 1 H NMR. The conversion level of methyl acrylate at this stage was 93% as estimated by 1 H NMR. The volatiles (2-methyltetrahydrofuran, t t-BuOH, and remaining methyl acrylate) were then removed under vacuum, recovering 27 g of methyl acrylate. The desired dimethyl 2-methylene glutarate was then distilled under vacuum (160°C, 15 mbar) to recover 284 g of analytically pure product, corresponding to a 75% isolated purification yield. The high-boiling by-products (mainly methyl acrylate oligomers) remaining in the distillation vessel amounted to 49 g (13%).

[0111] h) in tert-butanol (1 : 4 v / v t BuOH : methyl acrylate = 0.24 mol ( t BuOH) / mol (acrylic acid) NMR spectra: ​

[0112] All reactions were performed in carefully dried vessels and under an inert argon atmosphere. Methyl acrylate, tert-butanol, and diethylamine were dried using 4A molecular sieves, and the tert-butanol was distilled under argon before each reaction. Dichlorophenyl phosphine was used as is.

[0113] To a 50 mL two-necked round-bottomed flask were added: • 20 mL of 2-methyltetrahydrofuran • 5.43 mL of dichlorophenyl phosphine (7.17 g, 0.04 moles, 0.009 equivalents).

[0114] To a 100 mL three-necked round-bottomed flask equipped with a magnetic stirring device were added: • 20 mL of 2-methyltetrahydrofuran • 16.6 mL of diethylamine (11.7 g, 0.16 moles, 0.036 equivalents) (4 equivalents relative to dichlorophenyl phosphine).

[0115] Under stirring (1400 rpm), a 2-methyltetrahydrofuran solution of dichlorophenyl phosphine was gradually added to the diethylamine solution over 1 h while keeping the temperature of the reaction medium below 40°C (exothermic reaction). A white precipitate corresponding to the diethylammonium chloride salt by-product was formed upon addition of dichlorophenyl phosphine. At the end of the addition of dichlorophosphine, the mixture was then stirred at ambient temperature and the reaction progress was monitored by NMR.

[0116] Upon completion of the formation of bis-(diethylamino)phenyl phosphine, which required 1 h of stirring at room temperature after the addition of dichlorophenyl phosphine, the mixture was filtered via a cannula into a 500 mL double-jacketed reactor maintained at 30°C, equipped with a temperature probe, a condenser and a mechanical stirrer (propeller with four tilted plows) and containing: • 100 mL of distilled tert-butanol (1 : 4 v / v tert-butanol : methyl acrylate) • 100 mL of methyl acrylate (95.2 g, 1.105 moles, 0.25 equivalents).

[0117] Then 300 mL of methyl acrylate (285.6 g, 3.315 moles, 0.75 equivalents) were gradually added to the reactor over 4 h. At the end of the addition, the mixture was then continuously stirred at 30°C for 16 h. The reaction progress was monitored by 1 H NMR. The conversion level of methyl acrylate at this stage was 92% as estimated by 1 H NMR.

[0118] The volatiles (2-methyltetrahydrofuran, t tert-BuOH and remaining methyl acrylate) were then removed under vacuum, recovering 29 g of methyl acrylate. Then, the desired dimethyl 2-methylene glutarate was distilled under vacuum (160°C, 15 mbar) to recover 288 g of analytically pure product, corresponding to a 76% isolated purification yield. The high-boiling by-products (methyl acrylate oligomers) remaining in the distillation vessel amounted to 49 g (13%).

[0119] i) in tert-butanol (1 : 8 v / v t BuOH : methyl acrylate = 0.12 mol ( t BuOH) / mol (acrylic acid) ​ ​

[0120] All reactions were performed in carefully dried vessels and under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried using 4A molecular sieves and the tert-butanol was distilled under argon prior to each reaction. Dichlorophenyl phosphine, diisopropylamine and pyrrolidine were used as received.

[0121] To a 50 mL two-necked round bottom flask were added: • 20 mL of 2-methyltetrahydrofuran • 3.6 mL of dichlorophenylphosphine (4.77 g, 0.027 mol, 0.012 equivalent).

[0122] Add the following to a 100 mL three-necked round-bottom flask equipped with a magnetic stirrer: • 20 mL of 2-methyltetrahydrofuran • 11.15 mL of diisopropylamine (8.05 g, 0.08 mol, 0.036 equivalents) (3 equivalents relative to dichlorophenylphosphine).

[0123] A solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was gradually added to a solution of diisopropylamine over 1 hour with stirring (1400 rpm) while keeping the temperature of the reaction medium below 40°C (exothermic reaction). The mixture was stirred at room temperature and 1 equivalent (0.027 mol, 1.92 g) of pyrrolidine was added to the reaction mixture. The reaction mixture was then stirred at room temperature for another hour to complete the formation of bis-(amino)phosphine.

[0124] The reaction mixture was filtered through a jacket into a 500 mL double-jacketed reactor equipped with a temperature probe, a condenser, and a mechanical stirrer (with four tilting plow propellers) and contained: • 25 mL of distilled tert-butanol (1:8 v / v tert-butanol: methyl acrylate) • 200 mL of methyl acrylate (190.1 g, 2.2 mol, 1 equivalent).

[0125] The mixture was then stirred continuously at 60°C for 19 hours. 1 H NMR was used to monitor the reaction process. 1 H NMR showed that the initial conversion of methyl acrylate was approximately 86 mol.

[0126] Distillation of volatiles ( t -BuOH, Me-THF and unconverted methyl acrylate), thereby recovering 20 g of methyl acrylate.

[0127] The desired product (dimethyl 2-methyleneglutarate) was then distilled under vacuum (125 °C, 7 mbar) to give 103 g of analytically pure product.

[0128] Then, 190 g of methyl acrylate (2.2 moles, 1 equivalent) were added to the residue still containing the active phosphine catalyst, followed by the addition of 20 g of tert-butanol. The mixture was stirred for another 16 h 00 at 60°C to convert the second batch of methyl acrylate. The volatiles were distilled off, recovering 37 g of methyl acrylate and the product was distilled under vacuum (125°C, 8 mbar) to obtain 126 g of analytically pure product.

[0129] Finally, another 190 g of methyl acrylate (2.2 moles, 1 equivalent) were added to the residue still containing the active phosphine, and the mixture was stirred for another 20 hours at 70°C. At the end of the reaction, the volatiles were removed under vacuum to recover 44 g of methyl acrylate, and the product was distilled under vacuum to obtain 91 g of pure product.

[0130] A total of 320 g of 2-methylene pentanediolic acid dimethyl ester product was recovered, corresponding to a global separation and purification yield of 56%.

[0131] This is the first example of an aminophosphine catalyst that can be recycled after the dimerization of acrylate esters.

[0132] j) presence / absence t Effect of i-PrOH All reactions were carried out in carefully dried vessels under an inert argon atmosphere. Methyl acrylate was dried using 4A molecular sieves. Dichlorophosphine and amines were used as received.

[0133] To a 25 mL two-necked round-bottomed flask were added: • 18 mL of 2-methyltetrahydrofuran • Dichlorophosphine precursor (10.5 mmol, 0.005 equivalents relative to methyl acrylate).

[0134] To a 50 mL three-necked round-bottomed flask equipped with a magnetic stirring device were added: • 6 mL of 2-methyltetrahydrofuran • 3 equivalents of diisopropylamine relative to the dichlorophosphine precursor (31.4 mmol).

[0135] The dichlorophosphine solution was gradually added to the amine solution over 1 hour under stirring (1400 rpm) while keeping the temperature of the reaction medium below 40°C (exothermic reaction). A white precipitate corresponding to the insoluble diisopropylammonium chloride salt by-product was formed upon addition of the dichlorophosphine to the amine solution. The mixture was then stirred at ambient temperature and the reaction progress was monitored by 31 P NMR. The formation of the intermediate chloro(diisopropylamino)phosphine was confirmed by 31 P NMR (e.g. a singlet was observed at +132.5 ppm for chloro(phenyl(diisopropylamino)phosphine).

[0136] After the formation of the chloro amino phosphine intermediate was complete (this typically required stirring at room temperature for 1 h after the addition of the dichlorophosphine), 1 equivalent of pyrrolidine (10.5 mmol) was added to the mixture at room temperature with stirring and the reaction mass was stirred at room temperature for a further 1 h.

[0137] After the bis-amino phosphine was complete, the mixture was then filtered via a cannula into a 500 mL double-jacketed reactor equipped with a mechanical stirrer (propeller with four tilted plows), a condenser, a heater, and a temperature probe and containing 190 mL of methyl acrylate (180 g, 2.1 moles). The mixture was then stirred continuously at 60 °C for 20 h. Then, by 1 HNMR The conversion of methyl acrylate was estimated by integration of the methylene protons of the product and the methylene protons in the starting methyl acrylate. At 66% conversion of methyl acrylate, the selectivity to the dimer was 78% as determined by H NMR. 1 H NMR The conversion of methyl acrylate was estimated by integration of the methylene protons of the product and the methylene protons in the starting methyl acrylate. At 66% conversion of methyl acrylate, the selectivity to the dimer was 78% as determined by H NMR.

[0138] In contrast, when the reaction was performed in the presence of t - t-BuOH (1 : 1 v / v t - t-BuOH : methyl acrylate), 0.5 mol% initial loading of dichlorophenyl phosphine, 60 °C (corresponding to the present invention 4.3), the selectivity to the dimer was 87% at a similar conversion level (66%), clearly demonstrating t the positive effect of t-BuOH on the selectivity of the reaction.

[0139] k) Loading of the methyl acrylate dimerization The reaction was performed in a carefully dried vessel and under an inert argon atmosphere.

[0140] The t-butanol solvent was flashed under argon prior to the reaction and the anisole was dried over activated molecular sieves 4A overnight prior to the reaction.

[0141] The reactants diethylamine and methyl acrylate were also dried over activated molecular sieves 4A overnight prior to the reaction.

[0142] K1) To a 250 mL double-jacketed reactor equipped with a temperature probe, a mechanical stirrer (propeller with four tilted plows), and a baffle at room temperature was added: - 40 g of anisole - 18.4 mL of diethylamine (12.98 g, 177 mmol).

[0143] A solution of dichlorophenylphosphine (DCPP) in anisole (previously prepared by dilution of 6.17 mL of DCCP at 97% purity (8.14 g, 44 mmol) in 30 g of anisole) was gradually added to a solution of diethylamine in anisole (exothermic) under stirring (500 rpm) at room temperature over 1 h.

[0144] During the addition, a precipitate (NH2Et2CI) was formed, resulting in a gel-like solution. At the end of the addition, an additional amount of 30 g of anisole was added to the mixture to reduce the viscosity of the suspension and the reaction medium was continuously stirred at room temperature for 1 h 30. 31 P NMR analysis confirmed the complete conversion of DCPP into the desired bis(diethylamino)phenylphosphine at this stage.

[0145] The suspension was then easily filtered in a filtration unit under argon using a 6 pm filter cloth. The solid was washed with an additional 60 g of anisole. A total of 138.4 g of clear yellow solution as filtrate was obtained. The solution was quantified using triethyl phosphate as an internal probe 31 P NMR analysis determined the concentration of the aminophosphine catalyst in the solution: 4.6 wt%, corresponding to 6.3 g of catalyst (25 mmol), which corresponds to a catalyst loading of only 0.28 mol% relative to methyl acrylate.

[0146] In a 1.5 L double-jacketed reactor equipped with a condenser, a temperature probe, a mechanical stirrer (propeller with four tilted plows) and baffles, 157.8 g of tert-butanol (200 mL) were added, followed by the previous anisole solution of the catalyst (138.4 g). The solution was then stirred (500 rpm) at 40°C and 760 g of methyl acrylate (8.828 moles) were gradually added to the solution over 4 h 00 (exothermic). At the end of the addition of methyl acrylate, the reaction mixture was stirred overnight at 40°C and the reaction progress was followed by quantitative GC chromatography.

[0147] The conversion of methyl acrylate was followed as a function of time (as well as the dimer yield), and the kinetic curves are presented in the following graph (left: conversion of methyl acrylate as a function of time; right: dimer yield as a function of time). As can be seen in the graph below (black curve), a final conversion of 66% was obtained after 24 h 00 at 40°C with only a catalyst loading of 0.28 mol%, corresponding to a dimer yield of 58%.

[0148] K2) At room temperature, to a 250 mL double-jacketed reactor equipped with a temperature probe, a mechanical stirrer (propeller with four tilted plows) and baffles, were added: - 40 g of anisole - 25.7 mL of diethylamine (18.17 g, 247 mmol).

[0149] A solution of dichlorophenylphosphine (DCPP) in anisole (previously prepared by dilution of 8.44 mL of DCCP at 99% purity (11.13 g, 62 mmol) in 30 g of anisole) was gradually added to the diethylamine solution over 1 hour at room temperature under stirring (500 rpm) (exothermic).

[0150] During the addition, a precipitate (NH2Et2CI) was formed, resulting in a gel-like solution. At the end of the addition, the reaction mass was continuously stirred at 40°C for 30 minutes. 31 P NMR analysis confirmed the complete conversion of DCPP to the desired bis(diethylamino)phenylphosphine at this stage.

[0151] The suspension was then filtered via cannula into an intermediate flask and the solid was washed with a further 90 g of anisole. A total of 153.7 g of clear yellow solution was obtained. The solution was quantified using triethyl phosphate as an internal probe 31 P NMR analysis determined the concentration of the aminophosphine catalyst in the solution: 8.6 wt%, corresponding to 13.2 g of catalyst (52 mmol), which corresponds to a catalyst loading of only 0.6 mol% relative to methyl acrylate.

[0152] To a 1.5 L double-jacketed reactor equipped with a condenser, a temperature probe, a mechanical stirrer (propeller with four tilted plows) and baffles, 157.8 g of tert-butanol (200 mL) was added, followed by the previous anisole solution of catalyst (153.7 g). The solution was then stirred (500 rpm) at 40°C and 760 g of methyl acrylate (8.828 moles) was gradually added to the solution over 4 h 00. At the end of the addition of methyl acrylate, the reaction mixture was stirred overnight at 40°C and the reaction progress was followed by quantitative GC chromatography.

[0153] When following the change in methyl acrylate conversion (and dimer yield) over time and the kinetic profile, it can be seen that a final conversion of >99% is obtained after 25 h 00 at 40°C with only a 0.6 mol% catalyst loading, corresponding to a dimer yield of 82%.

[0154] K3) To a 250 mL double-jacketed reactor equipped with a temperature probe, a mechanical stirrer (propeller with four tilted plows) and baffles, at room temperature, were added: - 40 g of anisole - 25.7 mL of diethylamine (18.17 g, 247 mmol).

[0155] A solution of dichlorophenylphosphine (DCPP) in anisole (previously prepared by dilution of 8.44 mL of DCCP at 99% purity (11.13 g, 62 mmol) in 30 g of anisole) was gradually added to the diethylamine solution over 1 hour at room temperature under stirring (500 rpm) (exothermic).

[0156] During the addition, a precipitate (NH2Et2Cl) was formed, resulting in a gel-like solution. At the end of the addition, the reaction mass was continuously stirred at 40°C for 30 minutes. 31 P NMR analysis confirmed the complete conversion of DCPP into the desired bis(diethylamino)phenylphosphine at this stage.

[0157] The suspension was then filtered via a cannula into an intermediate flask and the solid was washed with additional 90 g of anisole. A total of 142.0 g of clear yellow solution was obtained. The solution was quantified using triethyl phosphate as an internal probe 31 P NMR analysis determined the concentration of the aminophosphine catalyst in the solution: 7.2 wt%, corresponding to 10.22 g of catalyst (41 mmol), which corresponds to a catalyst loading of only 0.46 mol% relative to methyl acrylate.

[0158] To a 1.5 L double-jacketed reactor equipped with a condenser, a temperature probe, a mechanical stirrer (propeller with four inclined plows), and baffles, 157.8 g of tert-butanol (200 mL) was added, followed by 760 g of methyl acrylate (8.828 moles). Under stirring (500 rpm, exothermic), the previously prepared anisole solution of the catalyst (142.0 g) was added to the solution. The solution was then stirred overnight at 40°C and the reaction progress was followed by quantitative GC chromatography.

[0159] The conversion of methyl acrylate (as well as the dimer yield) was followed over time, and the kinetic curve shows that a final conversion of 87% is obtained after 48h00 at 40°C with only a 0.46 mol% catalyst loading, corresponding to a dimer yield of 76%.

[0160] 2. ​ The substrate 2-methylene pentane-dicarboxylic acid dimethyl ester (50 g, 0.29 mol) obtained according to the dimerization reaction described hereinbefore (application 4.4) was first added to a 100 mL autoclave reactor equipped with a mechanical stirrer (Rushton turbine), followed by the addition of a Pd / C (3%) catalyst (powder, 51% moisture content, 1 g wet corresponding to 0.49 g dry, 1 wt% relative to the substrate). The reactor was then tightly sealed and purged 3 times with 20 bar of nitrogen, followed by 3 purges with 5 bar of hydrogen. The reaction mixture was stirred at 1400 rpm and the temperature of the reaction mixture was then set to 40°C. The reaction medium was then continuously stirred at 40°C, 5 bar of hydrogen pressure (1400 rpm) for 6 hours and the hydrogen consumption was followed over time.

[0161] At the end of the reaction (confirmed by the absence of hydrogen consumption), the reaction mixture was cooled at room temperature, the stirring was stopped and the autoclave was depressurized. The reactor was purged with nitrogen, the crude was removed from the reactor and the catalyst was removed by filtration. The product 2-methyl pentane-dicarboxylic acid dimethyl ester was obtained as a clear liquid after catalyst filtration (50 g, corresponding to a 99% yield) and was used as such.

[0162] 3. ​

[0163] To a 2 L double jacketed reactor equipped with a mechanical stirrer (propeller with four tilted plows), a baffle, a temperature probe and a distillation column connected to a receiver were added: - 700 g (4.07 mol, 1 equivalent) of 2-methylene pentane-dicarboxylic acid dimethyl ester - 879 mL of water (48.8 mol, 12 equivalents) - 95% sulfuric acid (9 mL, 16.6 g, 0.163 mol, 4 mol% relative to 2-methylene pentane-dicarboxylic acid dimethyl ester) which was added dropwise to the reaction mixture at room temperature through an addition funnel.

[0164] The mixture was then stirred at 120°C and the methanol produced was distilled off from the reaction medium to move the reaction equilibrium towards the desired methylene pentane-dicarboxylic acid. 1 The reaction progress was followed by H NMR analysis. During the course of the reaction, the methanol produced was distilled off from the reaction medium to move the reaction equilibrium towards the desired methylene pentane-dicarboxylic acid.

[0165] After 2h30 of stirring at 120°C, 1 The H NMR analysis indicated a slow conversion of the di-ester into di-acid, therefore an additional amount of sulfuric acid was added to the reaction mixture to speed up the kinetics: 2.26 mL (0.04 mol, 1 mol%) and the temperature of the mixture was increased to 130°C.

[0166] However, after 2 h of additional stirring at 130°C, the conversion of diester was still too slow, so 2.26 mL (0.04 mol, 1 mol%) of H2SO4 was added again to the reaction mass.

[0167] After 11 h 30 of stirring at 130°C, 1060 mL of water / MeOH mixture were distilled off and 50 mL of fresh water were added to the reaction vessel.

[0168] After 16 h 30 of stirring at 130°C, 1 H NMR analysis indicated that about 10 mol% of remaining unhydrolyzed ester functions and a large amount of polymer by-product were formed.

[0169] At this stage, the recovered distilled mass was 1195 g, containing 6 g of insoluble starting diester.

[0170] The temperature of the reaction medium was lowered to 80°C and 36 mL of 35 wt% aqueous NaOH solution (2 equivalents relative to H2SO4) were slowly added to the vessel to neutralize the catalyst (exothermic).

[0171] The reactor content, maintained at 80°C, was drained into a beaker while stirring constantly, and the mixture solidified into an increasingly hard white paste upon cooling.

[0172] 147 mL of water were added to the paste to obtain a filterable liquid paste, and the mixture was cooled at room temperature to complete the precipitation of the diacid product.

[0173] The product was then filtered through a sintered filter and a very viscous filtrate was obtained.

[0174] The filter cake was washed 4 times with 80 mL of water and then 6 times with 70 mL of water, shaking the mixture well before each filtration.

[0175] The resulting aqueous filtrate, which was left to precipitate overnight at room temperature, was filtered and washed 10 more times with 20 mL of water to collect additional product.

[0176] The solid fraction was collected, and the product was dried under vacuum at 50°C (10 mbar) for 2 hours, yielding 286 g of white powder with an organic matter purity exceeding 98 wt% and containing 3 wt% of water, which corresponds to a 48% isolated yield.

[0177] ​ 1H NMR (MeOD-d4, 400 MHz) δ (ppm): 6.16 (s, 1H), 5.63 (s, 1H), 2.6-2.56 (t, J=7.6 Hz, 2H), 2.51-2.47 (t, J=7.6 Hz, 2H).

[0178] 13 C NMR (MeOD-d4, 101 MHz) δ (ppm): 176.7, 170.12, 141.16, 126.38,34.07, 28.52.

Claims

1. A process for the production of a dimer according to formula (II), comprising the step i) dimerization of an alkyl acrylate according to formula (I) using a catalyst according to formula (III) according to the following reaction scheme to obtain a dimer according to formula (II): wherein R is an alkyl group; R1and R2are the same or different, an aliphatic group or form together with the N atom a heteroaliphatic ring; wherein the dimerization step i) is carried out in the presence of a compound A which is a tertiary alcohol or a silanol; and R a is a hydrocarbon group; R b is an aliphatic group or NR3R4, wherein R3and R4are the same or different and are aliphatic groups or together with the N atom form a heteroaliphatic ring; wherein an acid is added during the step i). Compound A is a tertiary alcohol, such as tert-butanol, tert-amyl alcohol or pinacol and more preferably tert-butanol.

2. The method of claim 1, wherein, The molar ratio [compound A] / [alkyl acrylate according to formula (I)] is selected from about 4 : 1 to about 0.01 : 1, preferably about 2 : 1 to about 0.1 : 1 and more preferably about 0.5 : 1 to about 0.1 :

1.

3. The method of claim 1 or 2, wherein, R1and R2are the same linear or branched alkyl group comprising 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, more preferably ethyl.

4. The method of any one of claims 1 to 3, wherein, R is C1-C 18 , preferably C1-C8 alkyl, more preferably C1-C4 alkyl, and most preferably methyl.

5. The method of any one of claims 1 to 4, wherein, R1and R2form together with the N atom a heteroaliphatic ring comprising 3 to 5 carbon atoms, preferably 4 carbon atoms.

6. The method of any one of claims 1 to 4, wherein, The dimerization step i) is carried out in an organic solvent, preferably an aprotic solvent, more preferably selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, dioxane, pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, benzene and acetonitrile, still more preferably MeTHF and toluene.

7. The method of any one of claims 1 to 6, wherein, R a is an aromatic or aliphatic radical, preferably an aromatic radical, more preferably selected from the group consisting of phenyl, tolyl, xylyl, mesityl, cumyl, pentamethylphenyl, 2,6-diisopropylphenyl, t-butylphenyl, di-t-butylphenyl, methoxyphenyl, dimethoxyphenyl, methoxytolyl, methylenedioxyphenyl, biphenyl, nitrophenyl, halogen substituted phenyl, trifluoromethylphenyl, naphthyl, pyridyl, furanyl, pyrrolyl, thienyl, 2-indolyl, benzofuranyl, and all positional isomers thereof.

8. The method of any one of claims 1 to 7, wherein, R b is NR3R4, wherein R3and R4are the same or different and are aliphatic groups or form together with the N atom a heteroaliphatic ring, preferably R3and R4are the same linear or branched alkyl group comprising 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, most preferably ethyl.

9. The method of any one of claims 1 to 8, wherein, R a is phenyl, R1and R2are ethyl and R b is NR3R4, wherein R3and R4are ethyl.

10. The method of any one of claims 1 to 9, wherein, The dimerization step i) is carried out at a temperature ranging from about 20 °C to about 120 °C, preferably from about 20 °C to about 80 °C, more preferably from about 25 °C to about 60 °C.

11. The method of any one of claims 1 to 10, wherein, 12. The process according to any one of claims 1 to 11, further comprising an initial step 0) of preparing the catalyst according to formula (III) by reacting a compound according to formula (IV) (IV) wherein X is chlorine, bromine or iodine, preferably chlorine; with Step 0) and step i) are consecutive steps carried out without isolation of the catalyst after step 0). R a is as defined in any one of claims 1, 7 or 9; R c is X or R b wherein R b is as defined in any one of claims 1, 8 or 9; 14. A process for the production of a compound according to formula (VI), comprising the process according to any one of claims 1 to 13 followed by step ii) hydrogenation of the dimer according to formula (II) obtained in the dimerization step using H2and a hydrogenation catalyst, such as a Pd-based catalyst, a Ru-based catalyst, a Pt-based catalyst, a Co-based catalyst, a Rh-based catalyst, an Ir-based catalyst and a Ni-based catalyst, to obtain a compound of formula (VI), - when R c is R b , an amine of formula V: R1R2NH (V), wherein R1and R2are as defined in any one of claims 1, 5, 6 or 9, or - when R c is X, both the amine of formula (V) and the amine of formula (V’): R3R4NH (V’), wherein R3and R4are as defined in any one of claims 1, 8 or 9.

13. The method of claim 12, wherein, wherein R is as defined in claim 1 or 4. ​ ​ 15. A process for the production of a compound according to formula (VII), which process comprises a process according to any one of claims 1 to 13, followed by the step ii') hydrolysis of the dimer according to formula (II) obtained in the dimerization step using an acid catalyst such as a Lewis acid or a Brønsted acid to obtain a compound of formula (VII) ###0007### (VII) 。 16. A process for the production of a compound according to formula (VII’), (VII’), The process comprises the process as claimed in claim 14, followed by step iii) reacting the compound of formula (VI) 5 R 6 with an amine of formula HNR 5 and R 6 are identical or different and each is selected from a saturated or unsaturated, straight-chain or branched, optionally cyclic, optionally aromatic, optionally substituted hydrocarbon-based radical having an average number of carbon atoms ranging from 1 to 36, with the proviso that R 5 and R 6 may optionally together form a ring member, which is optionally substituted and / or optionally contains a heteroatom; preferably R 5 = R 6 = methyl.

Images